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Intra-prefrontal cyclosporine potentiates ketamine-induced fear extinction in rats

Abstract

Several brain regions, including the medial prefrontal cortex (mPFC), are important in the process of fear extinction learning. Ketamine is a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, which is shown to play a role in extinction modulation. Ketamine and calcineurin (CN), an intracellular protein phosphatase, have several common targets in the cells. Therefore, in the present study, our aim is to investigate the possible role of calcineurin in the mPFC on the enhancing effects of ketamine in fear extinction. First, different doses of a CN inhibitor, cyclosporine-A (CsA), were micro-injected into the infralimbic (IL) region of the mPFC prior to extinction training in a classical conditioning model in rats. Next, sub-effective doses of CsA (Intra-mPFC) and ketamine (i.p.) were co-administered in another cohort of rats to find their possible interactions. Enzymatic activity of calcineurin was measured in the IL-mPFC following drug administration. We used the elevated plus-maze (EPM) and open field (OF) test for further behavioral assessments. The results showed that CsA can enhance the extinction of conditioned fear and inhibit the enzyme CN at a dose of 20 nM. The combination of sub-effective doses of CsA (5 nM) and ketamine (10 mg/kg) could again enhance the extinction of fear and reduce CN activity in the region. Our results propose that inhibition of CN in the IL-mPFC is involved in the extinction of fear and ketamine enhancement of extinction is probably mediated by reducing CN activity in this part of the brain.

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Data available upon reasonable request.

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Acknowledgements

The content of this paper is extracted from the Pharm. D thesis submitted by Negin Tamasoki which was financially supported (Grant no. 980137) by the Deputy for Research and Technology of Kermanshah University of Medical Sciences, Kermanshah, I.R. Iran.

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AMF and NT: conceptualization, designed of the experiments, data collection, writing the first draft. RR: conceptualization, data analysis, editing. All the authors critically reviewed the contents and approved the final version of the manuscript.

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Correspondence to Ahmad Mohammadi-Farani.

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Animal experiment protocols were approved by the local ethical committee (ethical code, IR.KUMS.1397.849).

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Mohammadi-Farani, A., Tamasoki, N. & Rahimian, R. Intra-prefrontal cyclosporine potentiates ketamine-induced fear extinction in rats. Exp Brain Res 239, 1401–1415 (2021). https://doi.org/10.1007/s00221-021-06050-7

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Keywords

  • Ketamine
  • Cyclosporine-A
  • Medial prefrontal cortex
  • Fear extinction